Axon regeneration is a fundamental and conserved property of nervous systems. But although axon regeneration can restore function after nerve injury, regeneration often fails. Thus, a key question in the field is to discover what determines the regenerative capacity of injured neurons. This proposal investigates new mechanisms that function in the injured neuron and that help determine whether or not regeneration occurs. The long-term goal is to gain a comprehensive understanding of the cellular functions that link neuronal injury to successful regeneration. The specific goal of this project is to analyze three novel and interrelated mechanisms that regulate axon regeneration at the genetic, cellular, and molecular level. The project uses a combination of in vivo approaches that culminate in analysis of the injury response in individual neurons. The central hypothesis is that the three novel mechanisms act in a pathway that regulates axon regeneration and the neuronal injury response. However, each Aim is independent and will result in fundamental discoveries about the cell biology of axon regeneration even if the individual mechanisms operate in parallel rather than in a linear pathway. Each Aim is supported by extensive preliminary data, as well as by novel biological concepts and experimental approaches. Completion of these Aims will describe fundamental cellular mechanisms that mediate axon regeneration.